Pyrazolecarboxylic acid derivative, such as 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, is the key intermediate in the preparation of fungicides.
Document JP-2000-044541 reports that, in the presence of a base, the corresponding substituted pyrazoles with carboxylic acid dialkyl esters such as dimethyl sulfate, diethyl sulfate were N-methylated to give N-substituted pyrazole, and then after a series of reaction to give pyrazolecarboxylic acid derivatives. However, because of the toxicity of dialkyl sulfate, it is difficult to apply this preparation process on a large scale.
China Patent CN101044116A provides a preparation process that uses trialkylphosphate in place of virulent dialkyl sulfate. Yet this preparation process requires an 18-24 hours reaction under 180-200° C. high temperature. Moreover, it produces large amounts of waste water in the process of post-processing, which makes it do not fulfill the environmental requirements.
JACS, 73,3684 (1951) describes that, (2-ethoxy-methylene)-4,4-difluoro-methyl ethyl acetoacetate, which was obtained by reacting ethyl 4,4-difluoro-3-oxobutyrate with triethyl orthoformate and acetic anhydride, and then was reacted with a hydrazine derivative to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, which then was hydrolyzed to give the corresponding hydrolysis product. However, ethyl 4,4-difluoro-3-oxobutyrate is expensive and the yield of this method is less than 70%.
As introduced above, the prior art of preparation process of pyrazolecarboxylic acid derivative exists many issues, such as the use of toxic materials, the difficulty of waste treatment resulted in environmental pollution.